Method of deposition a dry powder and dispensing device

ABSTRACT

A dry powder, for example, a medicament for an inhaler, comprises elongated particles with an aspect ratio sufficient to cause the particles to be bound to a preferably metal or non-metallic sheet material substrate at the particle tips by electrostatic deposition and for aligning a plurality of particles with their major axes aligned normal to the substrate and oriented tip-to-tip. Particles deposited form a low density, high relative void deposition to minimize attractive forces between the particles. This minimizes agglomeration and bonding forces to the substrate facilitating the release of a powdered medicament in an inhaler. Medicament dosages in a substrate pocket are covered by a sealing layer. An embodiment of a drug dosage inhaler substrate and inhaler is disclosed.

This invention relates to a method of depositing dry powders on asubstrate, and in particular, medicaments for use with inhalers, forexample, and inhaler devices for use with such substrates.

CROSS REFERENCE TO RELATED APPLICATIONS AND PATENTS

Of interest are co-pending applications Ser. No. 08/661,213 entitledInhaler Apparatus with Modified Surfaces for Enhanced Release of DryPowders filed Jun. 10, 1996 in the name of Datta et al. now U.S. Pat.No. 5,871,010, Inhaler Apparatus with an Electronic Means for EnhancedRelease of Dry Powders Ser. No. 08/661,212 filed Jun. 10, 1996 in thename of Sun et al., Ser. No. 08/932,489 entitled Dry Powder DeliverySystem filed Sep. 18, 1997 in the name of Leedom et al., Ser. No.08/467,647 entitled Apparatus for Electrostatically Depositing andRetaining Materials Upon a Substrate filed Jun. 6, 1995 now U.S. Pat.No. 5,669,973, Ser. No. 08/506,703 entitled Inhaler Apparatus for Usinga Tribo-Electric Charging Technique filed Jul. 25, 1995 now U.S. Pat.No. 5,642,727, Ser. No. 08/659,501 entitled Methods and Apparatus forElectrostatically Depositing a Medicament Powder Upon Predefined Regionsof a Substrate filed Jun. 6, 1996 in the name of Pletcher et al., Ser.No. 09/095,246 entitled Dry Powder Deposition Process filed Jun. 10,1998 in the name of Poliniak et al., all of the foregoing being commonlyowned, Ser. No. 09/095,616 entitled Pharmaceutical Product and Method ofMaking filed Jun. 10, 1998 in the name of Chrai et al., the latter beingcommonly owned with the assignee of the aforementioned applications andthe assignee of the present invention, and U.S. Pat. Nos. 5,714,007,5,642,727, 5,669,973 commonly owned with the aforementionedapplications. All of the aforementioned are incorporated by referenceherein in their entirety.

Dry powder inhalers are used as drug delivery devices for pharmaceuticalcompounds to individuals. In these devices, a pharmaceutical powder isdeposited on a surface of a substrate. The substrate may then besupplied in the inhaler as a cassette, a cartridge and so on. When thepatient requires medication, the ideal dry powder inhaler forms a fineparticle cloud that is to be inhaled and thereby delivers a highrespirable fraction of the stored dose deeply into the patients lungs.In most cases, the deep recesses of the lung is the desired site for thedrugs in the inhaled powder cloud.

This can be most efficiently achieved by:

1. Releasing a high fraction of the deposited drug and

2. Insuring that the powder cloud consists of individual particles orparticle aggregates between 1 μm and 5 μm.

As individual particles are reduced below 10 μm, both release andparticle aggregation become serious hindrance to delivering a highrespirable fraction deeply into the patient's lungs.

A common problem dealt with by various prior art inhaler apparatuses fordispensing dry powder medicaments is providing for a controlled reliablerelease of the medicament. The dry powder inhalers may be loaded withmedicaments by filling techniques not involving electrostatics. Incertain implementations, the deposited powder tends to form agglomeratedparticles resulting in uncontrolled variation in the amount ofmedicament released. Several of the aforementioned applications providevarious solutions to this problem.

Numerous approaches have been taken in the design of dry powderinhalers. In some cases, the powder is released by impact of a substratepowder carrier, as disclosed in WO 93/09832. Of interest is an inhaleras disclosed in WO 90/13328.

In copending applications Ser. Nos. 661,213 and 661,212, indentations orraised surfaces are disclosed in the inhaler interior surfaces havingcontact with the medicament for inhalation, the surfaces minimizing thearea of contact between the medicament and the surfaces of the inhalerapparatus, promoting the release of the medicament from the inhaler.

Where particles of medicament agglomerate, they impact the mouth andthroat rather than remain in the air flow for deposition in the lungs.One remedy is to provide tortuous channels in the inhalers to promotedeagglomeration. However, the medicament may be deposited along thechannels leading to inaccurate dosage dispensing. Agglomeration alsoresults in the inhaler tending to dispense the medicament inaccuratelyso that greater or lesser amounts are dispensed. The aforementionedsolutions to the problem of agglomeration tend to rely on mechanicaldevices for minimizing agglomeration effects.

The small particle size required for transport to the lung presents anumber of problems for release by the inhaler and delivery to deep lungregions. As the particle size decreases, the relative bonding forcebetween the particle and other objects increases. This applies to bothparticle-to-substrate bonding and particle-to-particle bonding. As aresult, particle aggregates become more tightly bound and individualparticles are more difficult to remove from the substrate. Aggregationincreases the effective size of the drug released and diminishes therespirable fraction. The increase in relative particle-to-substratebonding makes drug release more difficult and also decreases therespirable fraction.

The present inventors recognize a need for a different approach whereinthe agglomeration itself is minimized so as to be negligible. Thisreduces the need for mechanical solutions to deal with the agglomerationeffects.

A method of depositing a dry powder on a substrate according to thepresent invention comprises providing a plurality of elongated dryparticles each having a longitudinal axis and depositing the particleson a surface of a substrate with the longitudinal axes alignedsubstantially normal to the substrate surface.

Preferably the method includes in one embodiment charging the particleswith a given polarity and electrostatically depositing the particles onthe substrate.

In a further embodiment, the particles are provided with an aspect ratiosuch that an electrical dipole is created in the particles along theaxis. An electrical field attracts the particles to the substrate.

In a still further preferred embodiment, the particles have an aspectratio of about 2:1.

The substrate may be metallic, or non-metallic including mesh andnon-mesh materials.

In a further embodiment, a controlled amount of the medicament isdeposited at each of a plurality of predetermined regions on the surfaceof the substrate.

The particles in a further preferred embodiment have a diametricaldimension in the range of about 0.5 μm to 3 μm and a length in the rangeof about 1 μm to 10 μm.

In a further embodiment, the particles are a pharmaceutically activeingredient medicament.

A device for dispensing a pharmaceutical drug according to a furtherembodiment of the present invention comprises an inhaler having amouthpiece and a medicament cavity in communication with the mouthpiece.A dry powder medicament deposited in discrete spaced locations on asubstrate is introduced into the cavity for selective dispensing by theinhaler, the medicament comprising a plurality of elongated particles,the particles having an aspect ratio such as to create an electricaldipole in the particles when charged or induced by the depositing field.

A device according to a still further embodiment of the presentinvention for depositing a dry powder on a substrate comprises aplurality of elongated dry particles each having a longitudinal axis andmeans for depositing the particles on a surface of a substrate with thelongitudinal axes aligned substantially normal to the substrate surface.

IN THE DRAWING

FIG. 1 is a schematic diagram illustrating in general form a depositionprocess for depositing particles according to an embodiment of thepresent invention;

FIG. 2 is a more detailed view of the diagram of FIG. 1 showing fieldgeneration on the substrate.

FIGS. 3 and 4 are electronmicrographs illustrating particles depositedon a substrate according to an embodiment of the present invention;

FIG. 5 is a side sectional elevation view of an exemplary inhalerincorporating a medicament deposited according to the present invention;and

FIGS. 6 and 6a are side elevation fragmented sectional views of arepresentative substrate employed in an inhaler apparatus of anembodiment of the present invention.

In FIG. 1, deposition system 30 is diagrammatically shown and comprisesa substrate 32, a charge source 34 for generating a field represented bydashed lines 36, a control 38 and a medicament cloud generator 40 forgenerating a cloud of elongated medicament particles 42. Generallyelectrostatic deposition systems are known as described in theaforementioned copending applications and patents. However the disclosedsystems may be modified as described herein according to the presentinvention.

In diagrammatic FIG. 2, in one embodiment, the substrate 32 is at onepolarity, e.g., negative charged, and a field electrode 44 is at theopposite polarity, e.g., positive charged. Electrode 44 may surround thesubstrate 32. Substrate 32 is charged at a local region for receivingthe medicament in controlled amounts as described for example in theaforementioned patents and copending applications mentioned in theintroductory portion and incorporated by reference herein. Field lines36 are created between the substrate 32 and the field electrode 44 asshown. Elongated particles 46 in the field exhibiting dipoles align withthe field lines 36 and wherein the charges on the substrate 32 attractthe particles 46 to the substrate 32.

The medicament powder is in the form of elongated particles having anapproximate diameter preferably in the range of about 0.5 to 3 μm and anaxial extent of preferably in the range of about 1 to 10 μm. Theparticles are charged with a given polarity in a conventional chargingmechanism such as triboelectric chargers, induction charging and so on.The particles are deposited in controlled amounts wherein the amount ofactive pharmaceutical ingredients deposited at each of a plurality oflocations on the substrate does not vary from a predetermined amount,for example, by more than 15%.

Reference is made to the copending applications Ser. No. 09/095,246entitled Dry Powder Deposition Process filed Jun. 10, 1998 in the nameof Poliniak et al. and Ser. No. 09/095,616 entitled PharmaceuticalProduct and Method of Making filed Jun. 10, 1998 in the name of Chrai etal. noted in the introductory portion and incorporated by referenceherein in their entirety. These applications disclose apparatus andprocesses for electrostatically depositing pharmaceutically activeingredient medicaments on a substrate including charging a dry powdermedicament and electrostatically attracting the charged powder particlesto a substrate. In particular, the medicament is deposited in controlledamounts at discrete locations on the substrate wherein the amountsdeposited do not vary from a predetermined amount by more than 15%, forexample. This process is preferred.

However, other processes for electrostatically depositing dry powdermedicaments on a substrate are also disclosed in the aforementionedcopending applications and patents noted in the introductory portion,all of which are incorporated by reference herein. Those processesdisclose electrostatically depositing controlled amounts of dry powdermedicaments on a substrate at discrete locations on the substrate.Variations of the disclosed process herein may be employed to adaptthose processes to a metal substrate, whether a tape, mesh or disk withradially extending fingers on which medicaments are deposited as will bedescribed below as employed in the present embodiments. Such variationsare within the skill of those of ordinary skill in this art.

In the present invention, elongated dry medicament particles are chargedwith one polarity, e.g., positive charges and electrostaticallydeposited on a substrate exposed to an electric field, with a spatialvariation arranged to attract the charged particles to discretepredetermined locations on a substrate. This is to be differentiatedfrom prior art processes wherein the particles tend to be generallyspherical, amorphous or symmetrical.

Particle removal from surfaces tends to be more difficult as particlesize decreases. This is roughly a consequence of the adhesion forcedecreasing more slowly than the volume and surface area as a particle'ssize decreases. Since the volume and surface are generally related toremoving forces and deaggregation, these forces become increasinglydifficult to overcome as the particle size decreases.

Forces of adhesion and agglomeration caused by van der Waal's forceincrease as the area of contact between a particle and substrate orbetween two particles increase. If highly elongated particles can bemade to deposit on substrates in such a manner that only their tipscontact a substrate, adhesion will be lower than if similar particlesdeposit with their long axes in contact with the substrate. Similarly,agglomeration forces between highly elongated particles will beminimized if they contact tip-to-tip. Agglomeration can also bedecreased if the particle density is sufficiently low as to inhibitparticle-particle contact along their major axes.

To obtain high respirable fractions, electrostatic deposition ispreferred to minimize particle-substrate and particle-particle contactwhich minimizes adhesive and agglomeration forces respectively. Most ifnot all pharmaceutical powders are dielectric and can support theseparation of electrical charges. In the presence of an electric field,such as the field manifested by lines 36, FIG. 2, particles of suchpowder tend to become electrically polarized forming dipoles. Theparticles do not need to be separately charged independently of thefield to form such dipoles.

That is, the elongated particles tend to form dipoles with a positivecharge at one tip and a negative charge at the opposite tip. A field isapplied to the substrate to attract particles charged with a positivepolarity, FIG. 2. When the particles are attracted to the substrate bythe electric field, the dipole charge in the particles aligns theparticles so that their major axis is generally normal to the substratesurface. This attracts the particle tips to the substrate via oppositepolarity charges in the substrate field and particle tip. The particlesthus stand upright end up on the substrate. FIGS. 3 and 4 areelectronmicrographs showing this end-to-end configuration. FIG. 3 showsthe grains of a deposited pharmaceutical product at a discrete locationon an aluminum substrate. The field aperture 50 outline is shown byscattered particles. The field-defined dose 52 has an open structure asshown in FIG. 3. A comparison of the dose size to grain size is shown bythe scale in the figure. FIG. 4 shows the columnar structure of thedeposited powder. The scale shows this is an enlargement relative to thescale of FIG. 3.

The higher the aspect ratio of the particles, the greater thepolarization. In turn, the polarization of highly acicular particlescauses an alignment of the particle's major axis with the electric fieldline. Introduced charges on insulated dielectric particles will dominatethe alignment of the particles.

By controlling the field's geometry, it is possible to align thepharmaceutical particles and direct their deposition to particularlocations. For a pre-charged particle, a uniform field will align theparticle depending upon its charge distribution. For particles in whichpolarization is induced by an electrostatic field, alignment will becontrolled by the particle geometry, i.e., the long axis is alwaysparallel to the field gradient, FIG. 2. Charged particles will tend tofollow field lines. Thus it is advantageous to have a high density offield lines terminating in the preferred deposition site.

FIGS. 3 and 4 show an example of polyethylene glycol (PEG)electrostatically deposited on an aluminum film substrate. Theindividual particles have an aspect ratio of at least about 2:1 orgreater, e.g., 10:1. Once a particle has been deposited, theelectrostatic field acts to direct subsequent particles to formelongated chains of tip-to-tip particles. A relative high density ofparticles on the substrate that may lead to agglomeration of particlesalong their major axes and may occur under relatively high depositionconditions.

The low-density deposition in which the particle chains remainindividually isolated or in single particle thick chains is an idealstructure for release and deaggregation. Individual particles are eitherbound to the substrate at their tip or to other particles tip-to-tip. Ineither case, the resultant geometry offers minimum area for van der Waalinteraction and subsequently a minimum in adhesive and agglomerationforces.

The density of electrostatic deposited particles is low (i.e., 0.1-0.4of bulk density) due to the repulsive forces between the particles withthe same charge polarity.

For applications requiring doses below approximately 100 μg, depositionsmay be made on substrate areas of approximately 50 mm² withoutsubstantial aggregate formation. Consequently, they are isolated or formsingle-particle-thick chains with low interparticle van der Waal forcesand release from the substrate at much lower forces than otherwise wouldoccur.

In FIG. 5, an inhaler apparatus 2, which is given by way of example inone embodiment, comprises a one-piece molded thermoplastic housing 4having a chamber 6. Other dispensing devices and apparatuses as known inthis art may also be employed for dispensing a dry powder activepharmaceutical ingredient medicament. Such other devices may includecassette or cartridge type dispensers.

A mouthpiece 8 may be molded one-piece with and extends from the housing4 and has a throat 10 in fluid communication with the chamber 6. Amedicament dispensing tape 12 is supplied by reel 14. The tape 12comprises a metal tape substrate 16, preferably stainless steel.Medicament 18 is deposited on the substrate 16 in controlled amounts ateach of a plurality of discrete spaced locations. A tape seal 20 coversand protects the medicament 18 on the substrate 16.

The seal 20 is removed by take up reel 22 and the emptied substrate istaken up by take up reel 24. A battery 26 operates an electronicmedicament release mechanism 28 (not shown in detail) but described incopending application Ser. No. 661,212 mentioned in the introductoryportion and incorporated by reference herein. The inhaler apparatushousing 4, mouthpiece 8, substrate and related mechanisms are describedmore fully in copending application Ser. No. 661,213 mentioned in theintroductory portion and incorporated by reference herein.

The substrates may be employed in cassettes or cartridges and may beeither metal, e.g., stainless steel, or non-metallic as known in thisart, may be mesh or solid, and may be of any material suitable as amedicament substrate. The selection of a substrate material depends upona given implementation. In FIG. 6, substrate 16' may comprise a steeltape having a dosage 18 in discrete locations, a spacer 19 and a sealingtape 20. In the alternative, in FIG. 6a, pockets 19, or dimples (notshown) may be formed in the substrate 16". The pockets recesses thedosage 18 and avoids the need for a spacer. This recessing spaces thedosage 18 from the sealing tape 21. When the tape is removed, the dosageremains in place and is not removed by the tape.

It will occur to one of ordinary skill that modifications may be made tothe disclosed embodiments without departing from the scope of theinvention as defined in the appended claims. For example, the depositedpowder may not be a medicament, but may be powders for otherapplications in accordance with a given implementation. The varioussubstrates are also given by way of illustration. The dispensing deviceis also by way of example, as other dispensing arrangements may beemployed as desired. The description given herein is by way ofillustration and not limitation.

What is claimed is:
 1. A method of depositing dielectric elongatedpharmaceutical active medicament dry powder particles on a substratecomprising:providing a plurality of said dielectric elongatedpharmaceutical active medicament dry particles each having alongitudinal axis; and depositing the particles on a surface of thesubstrate with the longitudinal axes aligned substantially normal to thesubstrate surface, the particles being attracted to the substrate by anelectric field so as to minimize agglomeration of the particles and tominimize adherence of the particles to the substrate.
 2. The method ofclaim 1 including charging the particles with a given polarity andelectrostatically depositing the particles on the substrate.
 3. Themethod of claim 2 including providing the particles with an aspect ratiosuch that an electrical dipole is created in each particle along itslongitudinal axis such that an electrical field electrostaticallyattracts and aligns the particles to the substrate.
 4. The method ofclaim 1 wherein the particles have an aspect ratio of about 2:1.
 5. Themethod of claim 1 including providing a metal substrate.
 6. The methodof claim 5 including providing a stainless steel substrate.
 7. Themethod of claim 1 including depositing a controlled amount of theparticles at each of a plurality of predetermined regions on the surfaceof the substrate to form a unit dosage at each said predeterminedregion.
 8. The method of claim 1 including the step of forming particlechains substantially normal to the substrate.
 9. The method of claim 1including providing particles with a diametrical dimension in the rangeof about 0.5 to 3 μm and a length in the range of about 1 to 10 μm. 10.The method of claim 1 including the step of providing a plurality of theparticles in a plurality of separate discrete locations on thesubstrate, each location forming a dosage.